Chikungunya virus (CHIKV) is a mosquito borne alphavirus, first isolated in Tanzania in 1952 that has caused sporadic outbreaks of predominantly rheumatic disease every 2-50 years, primarily in Africa and Asia. The largest epidemic of CHIKV disease ever recorded took place during 2004-2011, and involved an estimated 1.4 to 6.5 million cases and the first autochthonous CHIKV infections in Europe (Italy in 2007 and France in 2010). Imported cases were also reported in nearly 40 countries, including European countries, Japan, and the USA. The epidemic was associated with the emergence of a new clade of viruses, which were efficiently transmitted by Aedes albopictus, a mosquito vector that has seen a dramatic global expansion in its geographic distribution. CHIKV disease is characterized by acute and chronic polyarthritis/polyarthralgia, which is usually symmetric and often incapacitating and occasionally protracted. Other symptoms, such as fever, rash, myalgia, and/or fatigue, are often also present during the acute phase. The recent epidemic was also associated with atypical and severe clinical forms of CHIKV disease and some fatalities, which appeared to be restricted to the very young and elderly patients with comorbidities.
CHIKV particles contain three major structural proteins: glycosylated E1 and E2 envelope (env) proteins embedded in the viral membrane, and a non-glycosylated nucleocapsid protein. Based on similarity to other alphaviruses, E2 mediates receptor attachment, while E1 is a class II viral fusion protein. A third glycoprotein, E3, is associated with mature virions in some alphaviruses, but not others, while 6K protein, a membrane-associated peptide created by cleavage of the polyprotein to release E2 and E1, is incorporated into particles at a low level.
The organization of the alphavirus surface glycoproteins in particles has been defined using cryo-electron microscopy (cryo-EM), while the atomic structure of CHIKV glycoproteins was recently solved by x-ray crystallography both for mature particles and for immature p62 Env precursor polyprotein prior to furin cleavage. 240 copies each of three glycoproteins (E3/E2/E1) come together to form a protein coat with icosahedral symmetry and containing 80 spikes. The folding, transport to the surface and function of these glycoproteins relies on their correct interactions with each other. E1 consists of three β-sheet domains, termed I, II and III, while E2 contains three immunoglobulin-like domains (A, B and C, with A being at the N-terminus). In the complex, domain B lies at the membrane distal end and contacts E3, domain C is closest to the viral membrane, and domain A is in the center. E1 interacts laterally with E2 all along domain II, along with additional points of contact from other regions of E1. E1 contains an internal fusion loop at the tip of domain II, which in the mature structure exists as a β-hairpin lodged in a groove between domains A and B of E2. E3 also plays a role in protecting the fusion loop from premature exposure.
Treatment of CHIKV rheumatic disease usually involves non-steroidal anti-inflammatory drugs (NSAIDs) and/or simple analgesics, which can provide relief, but is often inadequate. Although a number of vaccine strategies have been, or are being, explored, there are currently no licensed human vaccines for any alphavirus. Nevertheless, it is clear that CHIKV neutralizing antibodies from infected humans or vaccinated monkeys can mediate protection prophylactically, or soon after exposure. Polyclonal immunoglobulins derived from humans recovered from CHIKV infection, when passively transferred into neonatal and interferon α/β receptor deficient (IFNAR−/−) mice protected these animals from CHIKV-induced viremia and mortality. Purified total IgG from monkeys immunized three times with a CHIKV virus-like-particle vaccine (containing E1 and E2) similarly protected IFNAR−/− mice from CHIKV viremia and mortality. A recent study described two monoclonal antibodies 5F10 and 8B10, which were isolated from CHIKV infected individuals. These antibodies specifically neutralized CHIKV and o'nyong'nyong virus (ONNV, a virus closely related to CHIKV), but none of the other alphaviruses tested. The 5F10 and 8B10 antibodies, when used in escape mutant studies were shown to recognize key residues in E2 (V216) and E1 (T101), respectively. The combination of 5F10 and 8B10 monoclonal antibodies were also shown to significantly delay CHIKV-driven lethality in mice deficient in IFNα/β and IFNγ receptors, and mature B and T cells.
Accordingly, there is a need for further treatments including, antibody treatments against CHIKV.
The present embodiments fulfill other needs as well and will be evident from the description contained herein.